No abstract

Progress in the study of Covid‐19 disease in rodents has been hampered by the lack of angiotensin‐converting enzyme 2 (ACE2; virus entry route to the target cell) affinities for the virus spike proteins across species. Therefore, we sought to determine whether a modified protocol of lipopolysaccharide (LPS)‐induced acute respiratory distress syndrome in rats can mimic both cell signalling pathways as well as severe disease phenotypes of Covid‐19 disease. Rats were injected via intratracheal (IT) instillation with either 15 mg/kg of LPS (model group) or saline (control group) before being killed after 3 days. A severe acute respiratory syndrome (SARS)‐like effect was observed in the model group as demonstrated by the development of a “cytokine storm” (>2.7 fold increase in blood levels of IL‐6, IL‐17A, GM‐CSF, and TNF‐α), high blood ferritin, demonstrable coagulopathy, including elevated D‐dimer (approximately 10‐fold increase), PAI‐1, PT, and APTT (p < 0.0001). In addition, LPS increased the expression of lung angiotensin II type I receptor (AT1R)‐JAK‐STAT axis (>4 fold increase). Chest imaging revealed bilateral small patchy opacities of the lungs. Severe lung injury was noted by the presence of both, alveolar collapse and haemorrhage, desquamation of epithelial cells in the airway lumen, infiltration of inflammatory cells (CD45+ leukocytes), widespread thickening of the interalveolar septa, and ultrastructural alterations similar to Covid‐19. Thus, these findings demonstrate that IT injection of 15 mg/kg LPS into rats, induced an AT1R/JAK/STAT‐mediated cytokine storm with resultant pneumonia and coagulopathy that was commensurate with moderate and severe Covid‐19 disease noted in humans.

No abstract

The intermediate filament protein desmin is essential for maintaining the structural integrity of sarcomeres, the fundamental unit of cardiac muscle. Diabetes mellitus (DM) can cause desmin to become dysregulated, following episodes of nitrosative stress, through the activation of the iNOS/mTOR/TIMP-1 pathway, thereby stimulating collagen deposition in the myocardium. In this study, type 2 diabetes mellitus (T2DM) was induced in rats. One group of animals was pre-treated with metformin (200 mg/kg) prior to diabetes induction and subsequently kept on metformin until sacrifice at week 12. Cardiac injuries developed in the diabetic rats as demonstrated by a significant (p < 0.0001) inhibition of desmin immunostaining, profound sarcomere ultrastructural alterations, substantial damage to the left ventricular tissue, collagen deposition, and abnormal ECG recordings. DM also significantly induced the cardiac expression of inducible nitric oxide synthase (iNOS), mammalian target of rapamycin (mTOR), and the profibrogenic biomarker tissue inhibitor of metalloproteinase-1 (TIMP-1). The expression of all these markers was significantly inhibited by metformin. In addition, a significant (p < 0.0001) correlation between desmin tissue levels/sarcomere damage and glycated hemoglobin, heart rate, iNOS, mTOR, and fibrosis was observed. These findings demonstrate an association between damage of the cardiac contractile unit—desmin and sarcomere—and the iNOS/mTOR/TIMP-1/collagen axis of fibrosis in T2DM-induced cardiomyopathy, with metformin exhibiting beneficial cardiovascular pleiotropic effects.

Metformin pretreatment ameliorates diabetic nephropathy induced by a combination of high fat diet and streptozotocin in rats.